Tachycardia-Induced Changes in Na ⁺ Current in a Chronic Dog Model of Atrial Fibrillation

Abstract

We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n = 6) and 42 days (P42, n = 5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n = 6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na+ current (INa) density was reduced by 28% at -40 mV (P < .0001, n = 59 cells). INa changes were even more decreased under P42 conditions, by approximately 52% at -40 mV (P < .0001): from -78.7 +/- 4.6 pA/pF (P0, n = 28 cells) to -37.7 +/- 3.0 pA/pF (P42, n = 43 cells). INa was significantly reduced at all voltages ranging from -65 to -10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean INa in each dog (r2 = .573, P < .001). We conclude that rapid atrial activation significantly reduces both conduction velocity and INa density. Since INa is a major determinant of conduction velocity, our data point to INa reduction as a potentially important mechanism contributing to the substrate for AF in this model.

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

“…This reduction in ICa L contributes to the loss of the action potential plateau in atrial myocytes. Reductions of INa have been noted in dogs with tachycardia-induced AF (Gaspo et al, 1997), but to date there is no evidence of a decreased INa in atrial myocytes from AF patients, although a positive shift in the steady-state inactivation curve has been described (Bosch et al, 1999). The inward rectifier IK 1 is increased at the current, protein and mRNA levels in atrial myocytes from AF patients (Bosch et al, 1999).…”

Intracellular Chloride Accumulation and Subcellular Elemental Distribution During Atrial Fibrillation

“…[1][2][3] Although the changes in ionic currents leading to electrical remodeling have been well studied, the cellular and subcellular concentrations and distribution of elements during AF remain unknown. 4,5 It is not clear how AF alters the normal homeostasis of biological elements such as sodium (Na), potassium (K), chloride (Cl), phosphorus (P), magnesium (Mg), and calcium (Ca). Previous studies examining changes in ionic current density and/or ion fluxes have used isolated hearts or single myocytes; however, the cellular elemental composition as it exists in vivo during AF has not been determined.…”

Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling

“…Gaspo et al 117,124 showed a reduction in CV in ATR dogs. However, CV measurements were done in the RPW, where we also didn't find significant differences in CV between CTL and ATR.…”

“…The varying results regarding CV changes in ATR substrate may point to the existence of multiple factors and changes that can affect CV. A decreased I Na would tend to decrease CV 124 , while a decreased ERP or an increased connexin expression 75,125,126 would have the opposite effect.…”